Characterizing the supraspinal sensorimotor control of walking using MRI-compatible system: a systematic review

Background The regulation of gait is critical to many activities of everyday life. When walking, somatosensory information obtained from mechanoreceptors throughout body is delivered to numerous supraspinal networks and used to execute the appropriate motion to meet ever-changing environmental and task demands. Aging and age-related conditions oftentimes alter the supraspinal sensorimotor control of walking, including the responsiveness of the cortical brain regions to the sensorimotor inputs obtained from the peripheral nervous system, resulting in diminished mobility in the older adult population. It is thus important to explicitly characterize such supraspinal sensorimotor elements of walking, providing knowledge informing novel rehabilitative targets. The past efforts majorly relied upon mental imagery or virtual reality to study the supraspinal control of walking. Recent efforts have been made to develop magnetic resonance imaging (MRI)-compatible devices simulating specific somatosensory and/or motor aspects of walking. However, there exists large variance in the design and functionality of these devices, and as such inconsistent functional MRI (fMRI) observations. Methods We have therefore completed a systematic review to summarize current achievements in the development of these MRI-compatible devices and synthesize available imaging results emanating from studies that have utilized these devices. Results The device design, study protocol and neuroimaging observations of 26 studies using 13 types of devices were extracted. Three of these devices can provide somatosensory stimuli, eight motor stimuli, and two both types of stimuli. Our review demonstrated that using these devices, fMRI data of brain activation can be successfully obtained when participants remain motionless and experience sensorimotor stimulation during fMRI acquisition. The activation in multiple cortical (e.g., primary sensorimotor cortex) and subcortical (e.g., cerebellum) regions has been each linked to these types of walking-related sensorimotor stimuli. Conclusion The observations of these publications suggest the promise of implementing these devices to characterize the supraspinal sensorimotor control of walking. Still, the evidence level of these neuroimaging observations was still low due to small sample size and varied study protocols, which thus needs to be confirmed via studies with more rigorous design.

Characterizing the supraspinal sensorimotor control of walking using MRI-compatible system: a systematic review

Background
The regulation of gait is critical to many activities of everyday life.Aging and age-related conditions (e.g., movement disorders [1], stroke [2], chronic pain [3], etc.) oftentimes diminish gait performance [4,5] and thus increase the risk of deconditioning, mobility decline, and falls [6,7] in the older adult population and those suffering from gait disorders (e.g., shuffling gait).Gait is regulated by a complex system that requires ongoing communication between peripheral neuromuscular circuitry [8] and numerous subcortical and cortical networks [9].In particular, when walking, somatosensory information obtained from mechanoreceptors throughout the body is delivered via peripheral nerves to the central nervous system, where it is processed and integrated with visual and vestibular feedback in numerous cortical and sub-cortical networks and used to develop and execute appropriate motor programs to meet ever-changing environmental and task demands [10].In addition to the issues in peripheral musculoskeletal systems (e.g., osteoporosis), age and age-related conditions (e.g., stroke and Parkinson's disease) oftentimes alters the functional characteristics of supraspinal elements (e.g., the brain cortical regions) of walking, resulting in gait disorders.Considerable effort has therefore been placed on the study of the supraspinal control of walking in order to understand the impact of aging and age-related conditions on locomotor control and to identify new targets for preventive and rehabilitative medicine in those suffering from diminished mobility.
Functional magnetic resonance imaging (fMRI) enables the characterization of neural activity with high spatial resolution and can thus provide insight into the supraspinal control of many important functions and behaviors [11].However, it is challenging to utilize MRI to characterize locomotor control because the individual's head is required to stay motionless throughout the scan.The majority of efforts to date have thus relied upon mental imagery to study the planning and thought of carrying out movements [12][13][14], or virtual reality to study the processing of visual feedback related to navigating an environment [15][16][17][18].This research, while important, provides very little information regarding brain-level, somatosensory processing or the sensorimotor control involved in walking [14,19].As a result, recent efforts have been made to develop MRI-compatible devices that simulate specific somatosensory and/or motor aspects of walking, while limiting movement of the head.Studies using these devices have indeed provided new insights to locomotor control.At the same time, however, there exists large variance in the design and functionality of these devices, and as such, inconsistent fMRI observations.We have therefore completed a systematic review to (1) summarize the design and functionality of MRIcompatible devices that have been developed to characterize the supraspinal processing of sensorimotor aspects of locomotion, and (2) synthesize available BOLD results emanating from studies that have utilized these devices.The knowledge provided by this work is expected to inform the design of future studies implementing these devices to characterize the supraspinal elements of gait regulation in those suffering from gait disorders.

Search strategy
A systematic literature search of PubMed, Web of science, EBSCO MEDLINE, SPORT Discus, Psych-Info, Cochrane library and Scopus was performed with the last search completed on August 27, 2022.The search field focused on the magnetic resonance imaging compatibility of the devices (i.e., MRI-compatible) and the synonyms for gait including lower-extremity motor paradigms that were considered as the clinical surrogates of gait.The following search terms were used to identify relevant literature in the database: ("magnetic resonance imaging compatible" or "MRI compatible") and ("gait" OR "walk" OR "step*" OR "ambul*" OR "locomot*" OR "lower limb movement" OR "pedal" OR "dorsiflexion" OR "plantarflexion" OR "ankle motion*" OR "foot sole pressure stimul*").A manual search of the bibliographic references of extracted articles and existing reviews was also conducted to identify studies that were not captured in the electronic searches.

Inclusion and exclusion criteria
The inclusion criteria were: (1) the device used in the study was MRI-compatible with mechanical structure enabling the control or adjustment of stimulation parameters (e.g., applied force, movement speed of stimulation); (2) the goal of the study or device development was to explore the functional characteristics of the supraspinal regions pertaining to walking-related sensorimotor stimuli.Manuscripts were excluded if they: (1) only contained a descriptive overview of the device design; (2) were systematic reviews, case reports, protocol papers, conference abstracts, or letters to the editor; and (3) were not written in English.

Data extraction and synthesis
Two authors (YH and JZ) independently performed data extraction, and when disagreement on the extraction of data/information was present, it was discussed with additional authors (DB and BM) until a consensus was achieved.The following data were extracted for each study: (1) device characteristics: simulation protocol of sensorimotor characteristics of gait, design of power supply, execution unit and control unit, materials used to develop the devices, accessories to minimize unwanted or extraneous motions, and the results of MRI compatibility test and the validation test of device performance; and (2) and study characteristics: the information of the study team (e.g., first author, year of publishing, country), participant characteristics, fMRI protocol and design, and the results of head-motion artifacts and fMRI BOLD signal analysis.

Study selection
The data summary and analysis were completed on November 10th, 2022.Figure 1 presents the flow diagram of study selection.Our initial search retrieved 1,027 articles from four databases and 13 additional articles from other sources (e.g., reference lists from original work and review articles).After the removal of duplicates and the screening of title, abstract, and full text for study design and outcomes, 26 original research articles were eligible and included in the systematic review.Reasons for exclusion in this phase included: not related to gait, not an fMRI study, prototype description only, or not an MRIcompatible device with mechanical structure enabling the control or adjustment of stimulation parameters.

Device design
The structure of included devices can be divided into three main parts: the power supply unit, the execution unit that is oftentimes placed in the MRI scan room, and the control unit placed outside the scan room (Fig. 2; Table 2).

Device compatibility with fMRI
MRI compatibility of seven out of the thirteen devices were tested via phantom-based imaging quality tests and reported in nine publications [20,21,31,34,36,37,42,43,45].Uniquely, the compatibility of one device was also tested when human participants were performing tasks (e.g., voluntary motion of the lower extremities with and without wearing the lower-extremity motion simulator ) [42,43].Specifically, two studies measured spatial signalto-noise ratio (SNR) [31,45]; two measured temporal SNR [36,37]; one measured both spatial SNR and temporal SNR [34]; one measured spatial SNR, the signal-tofluctuation-noise ratio (SFNR) and the field map mean [20]; one measured spatial SNR, SFNR and the field nonuniformities [21]; and the other two measured the signal intensity and dispersion [42,43] (Table 3).Additionally, both non-metallic materials including plastic, rubber, and polyvinyl chloride (PVC) and non-magnetic metal including aluminum, bronze, brass, and stainless steel were used to manufacture devices to ensure the MRI compatibility (Table 3).

Device functionality
The overarching goal of included devices was to simulate walking-related somatosensory and/or motor experiences of walking over ground, during the MRI scan, thereby enabling study of related brain activity.As such, devices were designed to apply somatosensory stimuli to the foot soles (N = 3), induce locomotor-like movements of the lower extremities (including single-joint movement of ankle (N = 4), and multi-joint movements (N = 4)), or induce locomotor-like movements of the lower extremities while simultaneously applying somatosensory stimuli to the foot soles (N = 2).Additionally, three devices were designed for passive participant engagement, seven for active engagement to initiate movements by participants, and the other three for both functionalities (Table 1).
Three devices were designed to apply somatosensory stimuli to the soles of one or both feet [20][21][22][23][24] that mimic the ground reaction forces (GRF) experienced when walking.Specifically, the foot-sole stimulation system was designed to apply a sinusoidal pressure waveform with a peak force of 200 N and in a range of frequency from 1 to 10 Hz to one region of one foot sole [20].Two other similar devices were designed to apply pressure stimuli to multiple areas of one or both soles: the dual-drive foot-sole stimulator was designed to apply programmable waveform-type stimuli reproducing the pressure waveforms of each participant as recorded during walking over an instrumented pressure insole prior to the scan [21]; the Korvit boot system was designed to   apply two different forms of stimulation including "gaitlike" and "chaotic" sequences [22][23][24].Eight devices were designed to enable locomotor-like movements of the lower extremities.Five of these devices were designed to induce single-joint movement (i.e., ankle dorsiflexion and plantarflexion) and three were designed to induce multi-joint movements.Of the five single-joint devices, two were designed to enable unilateral movement [25,30].The other three were created to enable either unilateral or bilateral ankle dorsiflexion and plantarflexion with unique functions: one device provided real-time feedback of plantar flexion exertion in order to have participants attempt to achieve target forces [26]; one device was created to enable synchronization of the angle and torque characteristics of ankle movements in order to ensure consistency of task performance across trials [29]; and a final device (i.e., Bra.Di.P.O) was created to induce passive ankle motion patterns [27,28].Of the three devices enabling multi-joint movements, the pedal device was created to induce movements at different speeds without the restriction of knee motion [31][32][33]; the cylindrical treadmill device was created to enable participants to perform stepping movements by moving their legs to rotate a cylinder [36]; and the pseudogait-MRCD consisted of a vertical treadmill connected to a triangular platform that was create to enable participants to perform voluntary step-like movements [34,35].
The final two devices were designed to enable locomotor-like movements of the lower extremities combined with extra somatosensory stimuli [26][27][28][29][30][31][32][33][34].Specifically, the MARCOS device was described as being actuated by two pneumatic cylinders: one attached to knee orthoses allowing predefined flexion and extension movements of each leg in the sagittal plane, and the other attached to the shoe rendering external loads of up to 400 N along the cranio-caudal body axis to the foot-sole [37][38][39][40][41].The LOMS device was created to enable three    degree-of-freedom motion of each leg and simultaneously applies the ground reaction force of walking to foot soles via the foot stimulating parts [42][43][44][45].

Validation of device performance
Device performance was assessed in eight devices (Table 3).The similarity between the pressure as experienced during over ground walking and those simulated by the devices was tested for one device [21]; theoretical outputs (e.g., the output calculated from the formula using preprogrammed parameters) and the results obtained from the actual tests were compared in two devices [20,28]; the performance of iterative learning in the controller for one (i.e., the shift/difference between the maximum phase of the expected and measured trajectories of position or force) [38]; and the reliability of motion (e.g., the mean amplitude of the torques) across different time points [29,30,40] and/or load levels [41] was tested for three.No such information was provided for the other five devices [22-27, 31-36, 39, 42-45].

Study characteristics
The 26 included fMRI studies were completed by 12 groups from nine countries.A total of 371 participants were included across studies.The sample size in the included studies ranged from one to 67.The sex of participants was reported in 17 of 26 studies.Twenty-five studies focused on healthy participants and one study focused on participants with brain damage due to stroke [33].Ten studies reported both the age range and average age (one of which was median rather than mean [30]) of participants, five reported only the age range, seven reported only the average age (one of which had only one participant [37]), and four did not report age information (Table 4).Only two of the 26 studies reported on safety testing.One reported that the safety of their device was examined in a previous iterative pilot testing, but did not report details of the safety test [29], and the other reported that it was confirmed that all components of the device were not attracted by a U-shaped neodymium magnet [45].
Twenty-three of 26 studies utilized a block-design fMRI paradigm and the remaining three studies utilized event-related designs [25,26,37].Eighteen of 26 studies reported the details of imaging processing procedure [20-26, 28-36, 39, 40], while such information is missing for the other eight.Specially, four of the 18 studies   Brain activity patterns showed similar BOLD responses across pace conditions though significant differences were observed in parietal and cerebellar regions.
The post/pre-central gyrus and Cb showed significant activity during the movements.
Nine movement paradigm, each executed 30 times for 10s (five steps for 0.5 Hz), interleaved by 5s rest.
The more "uncommon" the motor task and the more "active" and "challenged" the subject was, the more activity was elicited within the sensorimotor brain areas.Three modes, each with 9 trails.Each trial consisted of 30s moving followed by 10s rest.
Active stepping elicited significant activation in an extensive sensorimotor network including medial M1 and L.PMC as well as activation in the Vermis and R.Cb.Passive stepping elicited activation in medial M1 and PMA in the left cerebral hemisphere but not the Cb.
Stepping with assist-as-needed led to significant activations in the L.SM1 and bilaterally in the superior parietal lobe.
For the comparisons performed in the included studies, 17 of 26 studies compared the brain activation between different stimulation conditions (e.g., unipedal versus bipedal stimulation, active versus passive movement) [22, 24-30, 32, 35-38, 40, 41, 43, 44], one between the condition of using mechanical stimulation induced by the device only and the motor imagery task only [23], one between stroke cohort and age-matched healthy counterparts [33] under the same stimulation condition, one between movements with and without the device stimulation [42], and the other six perform the comparison between task and blank blocks [20,21,31,34,39,45].

The fMRI observations
The 26 included fMRI studies characterized the supraspinal activation in response to somatosensory stimulation, to locomotor-like movements of the lower extremities, or to locomotor-like movements of the lower extremities in combination with extra simultaneous somatosensory stimulation.Key fMRI results are presented in Table 4.
With respect to single-joint movements, Trinastic et al. [25], and Newton et al. [30], compared the brain activation in response to active (i.e., the participant performed the movement voluntarily) ankle dorsiflexion and plantarflexion.Both studies observed that the S1/ M1 and SMA were activated by both movements, and uniquely, other brain regions (e.g., right putamen) were activated only by dorsiflexion.Doolittle et al. [29], compared the activation in response to active unilateral and bilateral motions of the ankle joint, and observed that the activation was not significantly different between these two conditions.In another study [26], the participant was asked to complete one trial each of plantarflexion of left foot, right foot, or both feet against 15% of his/her maximum voluntary contraction lasting for 5 s.It was observed that compared to unilateral (i.e., left or right foot) plantarflexion, bilateral plantarflexion induced greater activation in multiple cortical and subcortical regions (e.g., S1/M1 and PMC).Two studies directly compared the brain activation in response to active and "passive" (i.e., the device imposed participant movement) ankle movement.The results of both studies suggested that both active and passive movement induced activation in sensorimotor and supplementary motor regions, and active movements uniquely induced activation in thalamic, frontal and cingulated regions, while passive movements induced activation in temporal and parietal areas [27,28].
With respect to multiple-joint movements, Promjunyakul et al. [33], completed a study consisting of people recovering from stroke.They observed that as compared to age-matched healthy controls, the activation induced by actively pedaling, especially in the SMA, PMA and Cb, was significantly lower in people recovering from stroke.Brain activation in response to active and passive multiple-joint movements was also examined in four studies, showing different observations.Jaeger et al. [39], observed that compared to passive movements, active movements induced higher activation of S1/M1, SMAproper, cingulate motor area, S2, Cb and putamen; in another study, Mehta et al., observed that compared to passive movements, active movements induced higher activation within Cb only [32]; Hollnagel et al., observed [38] that active movements elicited activation in a more extensive sensorimotor network; and Takahiro et al. [44], observed that the sensory regions of the brain as activated by passive movement was broader than the areas activated by active movement.Additionally, the association between the walking-related supraspinal activation and the parameters of the movement (i.e., pace or frequency of the motion) was examined in three studies.Specifically, Mehta et al. [32], reported that higher pedaling rate was associated with greater activation in S1/M1, SMA, and Cb; Toyomura et al. [36], showed that slower speed of stepping elicited more-extensive activity in sensorimotor cortex and Cb; and Martinez et al. [35], observed that the increase of stepping frequency was associated with a decrease in the activation of Cb.
With respect to the combined-type stimulation (i.e., locomotor-like movements applied simultaneously with somatosensory stimuli as controlled by the device), Ikeda et al. [43], observed higher level of activation within the motor regions and Cb as induced by the locomotor-like movements alone, as compared to the combined-type stimuli.Likewise, Hollnagel et al. [37], reported observations in one participant that the combined-type stimuli induced lower activation in SMA and PMC as compared to locomotor-like movements alone.In another study, Jaeger et al. [41], examined supraspinal activation when participants were performing stepping at different levels of force simulating the GRF experienced during real walking (i.e., 0% (no force), 20% and 40% of the individual's body weight).No significant difference of the activation in sensorimotor regions between different levels of force was observed.In the same study, the influences of active and passive movements were also compared.It was observed that across all levels of force applied to the foot soles, active movements induced higher activation in Cb compared to passive movements.In another study from the same team, it was observed that both active and passive stepping movements with a load of 40% of individual's body weight induce activation in the bilateral S1/ M1, SMA-proper and Cb [40].

Discussion
Thirteen different devices have been developed and implemented in fMRI studies.These previous works suggest a great promise to utilize these devices within the MRI environment to apply controlled walking-related stimuli to induce activation within multiple cortical and subcortical regions.Replication of results in many of the studies, however, was limited by small sample sizes, heterogeneity of the participant characteristics, and limited reporting of device validation, design, and fMRI compatibility.Future studies with larger sample size and rigorous design and validation testing are thus warranted to confirm and extend the observations from these publications on the characteristics of supraspinal control of gait in aging process and under the influences of age-related conditions via the implementation of these MRI-compatible devices.
In the included publications, device validation efforts have been made for stimulation performance of the devices, which are critical to the quality of neuroimaging data and the observations of brain activation.Several teams implemented adaptive control protocols based upon actuator performance [28], and/or utilized a iterative learning controller [38], to overcome the potential delay of work commands caused by the distance between the control unit (placed outside the scan room) and execution circuit [28,48].Future work (on pneumatic devices specifically) should consider working to reduce air loss in transmission via better sealing of the pistons, which would help to increase power and energy efficiency [49].Additionally, between-subject variance in the characteristics of the lower extremity (e.g., different strength and lengths of the lower extremity between participants) may influence the device performance across individuals; and in turn, the degree to which a given device accurately simulates one or more elements of walking is a critical factor influencing fMRI results [21,24].It is thus recommended that future efforts to develop devices that can provide person-specific stimulation to more closely mimic their unique sensory or sensorimotor experience of walking, with the help of independentlycontrolled pneumatic actuators combined with pressure sensors to provide real-time feedback of applied pressure (i.e., closed-loop control of the stimulation) [21].
Efforts have also been made for the fMRI compatibility of these devices.For example, the execution units, which were placed inside the scan room, were uniquely manufactured with nonmagnetic and nonconductive materials with the goal to ensure sufficient robustness and to produce accurate and reliable stimulation to the individual during the MRI.Another challenge of using functional MRI to study brain activation induced by lower extremity stimulation is that stimulating or moving the legs and/or feet is likely to induce head motion artifact, which may in turn diminish image quality.Included studies successfully restricted movements of the head and trunk by using foam blocks and straps, and/or placing the knees in a flexed position and supporting the leg with a platform or cushion [26,30,34,35].Advanced signal processing techniques were also implemented to mitigate the influence of motion artifact on data quality in some studies.One commonly-used technique was "sparse sampling imaging" [50], which has been proven to effectively minimize movement-related artifacts on image quality [31][32][33]39].With the help of these strategies, studies that have reported the result of head-motion artifacts showed that the artifacts were less than 3 mm (in some cases even < 1 mm), which would not alter the observation of the brain activation [51].It should be noted that most included studies only recruited healthy younger adult volunteer without overt neurological disorders (only one included individuals recovering from stroke), and the device performance and fMRI compatibility were not explicitly reported in seven of the included devices.It is thus worthwhile to explore and establish a thorough and standardized procedure to examine the device performance and MRI compatibility, and a validated protocol of data acquisition and processing, enabling the production of reproducible sensorimotor stimulation, and thus reliable observation of the brain's activation across individuals [38,48].
In general, across all of the included studies, fMRI results primarily linked walking-related sensorimotor stimulation to activation of S1/M1, SMA and Cb.These observations are not entirely aligned with those of previous neuroimaging studies using mental imagery of gait [23,[52][53][54].Uniquely, Labriffe et al., directly compared the activation of supraspinal regions in response to mental imagery of gait and gait-related foot stimulation in a group of healthy younger adults.It was observed that mechanical stimulation, as compared to imagery, induced significantly greater activation in multiple regions (e.g., bilateral S1/M1 (especially areas related to lower limb), insula and Cb).These observations thus highlight the value of implementing MRI-compatible devices to apply walking-related stimuli to the lower extremities that mimics real walking, which can provide novel insights into the supraspinal sensorimotor control of gait that cannot be otherwise fully captured.Moreover, the stimulation and/or movements created by the different types of devices included in this review (e.g., foot sole somatosensory stimuli, stepping, pedaling, etc.), often induced different patterns in terms of negative and positive task associations, as well as recruitment of different brain regions.Therefore, in future studies, the design and characteristics of stimuli type appears to be critical and should be carefully taken into consideration.
The level of neuroimaging evidence of the activation of the brain in response to the stimulation was relatively low due to small sample sizes of participants and high heterogeneity of participant characteristics within and across studies.For example, several pilot studies focused primarily upon healthy younger adults or those with poorly-defined or under-reported inclusion and exclusion criteria.On the other hand, available evidence suggests that it is in fact feasible to simulate different sensory and/or motor aspects of walking within the MRI scanner without interfering substantially with imaging quality.Additionally, some important details were missing in several of the included publications, such as the utilization of data processing techniques, which is critical to the fMRI results.For example, eight of the included studies did not report if they completed the removal of head motion artifact [28,37,38,[41][42][43][44][45].

Conclusion
In conclusion, this review comprehensively summarized the current research and development achievements of the MRI-compatible devices that simulate and provide the walking-related sensorimotor stimulation when people lie motionless during the MRI scan, and thus enable the characterization of the supraspinal sensorimotor control of walking (e.g., brain's responsiveness) via fMRI.The evidence provided by these publications suggest that it is promising to implement these devices in human study to help characterize the supraspinal control of walking.However, the small sample size of participants and varied study design limited the power of evidence.Therefore, well-powered studies with more rigorous study protocols are warranted to confirm the feasibility of implementing these devices in different populations and those preliminary observations reported here, facilitate comparison between studies, and ultimately, elucidate the supraspinal networks involved in control pertaining to the regulation of gait in relatively-healthy cohorts and in those suffering from age-or disease-related gait disorders [55,56].

Fig. 1
Fig. 1 The RISMA flowchart of publication screening.Abbreviation PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; fMRI: functional magnetic resonance imaging mode (active, passive and assistas-needed stepping).

Table 1 Device design and functionality Fig. 2 The conceptual diagram of device structure Device Reference Type of stimuli Participant engagement Accessories to limit motion of head and body
[45]da et al., 2012)[43](Takahiro et al., 2013)[44](Ikeda et al., 2015)[45]Enables to control joint angle trajectory and joint togue at each joint independently enables various active and passive movements of the user's lower extremities and has foot stimulating parts at its two soles to simulate floor reactive force.Abbreviation Bra.Di.P.O., brain discovery pneumatic orthosis; RPM, Revolutions Per Minute; pseudogait-MRCD, pseudogait-magnetic resonance compatible device; MARCOS, magnetic resonance compatible stepper; LOMS, lower-extremity motion simulator; GRF, Ground Reaction Force

Table 2
Information on the components of device

Table 3
Information on the compatibility of device

Table 4
The design of fMRI task and key findings